Formation of seeding-competent α-synuclein aggregates in parkin-deficient iPSC-derived human neurons
Loss-of-function mutations in PARK2 (parkin) cause early-onset familial Parkinson's disease (PD) and may also contribute to sporadic PD. While Lewy bodies, enriched in aggregated phosphorylated α-synuclein (α-Syn), are typical in PD, their presence in PARK2-mediated PD remains debated. Using human isogenic PARK2<sup>-/-</sup> induced pluripotent stem cell-derived neurons, we investigated α-Syn pathology under parkin deficiency. PARK2<sup>-/-</sup> neurons showed elevated intracellular aggregated and total α-Syn levels, increased α-Syn release, and higher levels of aggregation-inducing α-Syn seeds. These neurons also displayed more pSer129 α-Syn<sup>+</sup> inclusions, which were further enhanced by α-Syn preformed fibril (PFF) exposure. Moreover, we identified synaptic loss in the PARK2<sup>-/-</sup> neurons, exacerbated by PFF treatment, and dysregulated Ca<sup>2+</sup> homeostasis consistent with enhanced activity of the smooth endoplasmic reticulum Ca<sup>2+</sup>-ATPase (SERCA). Our data provide an important contribution to the debate on the role of α-Syn in the pathology of PARK2-related PD and challenge the view of PARK2-related PD as a non-synucleinopathy.
Authors
- Morten Blaabjerg (ORCID: https://orcid.org/0000-0001-6007-1861)
- Emil Gregersen (ORCID: https://orcid.org/0000-0003-3923-4405)
- Daniel Aghaie Madsen
- Brent J. Ryan (ORCID: https://orcid.org/0000-0002-6703-3718)
- Morten Meyer (ORCID: https://orcid.org/0000-0002-9571-1336)
- Justyna Okarmus (ORCID: https://orcid.org/0000-0001-8310-6553)
- Sissel Ida Schmidt (ORCID: https://orcid.org/0000-0003-4939-8155)
- Janne Fuglsang Hansen (ORCID: https://orcid.org/0000-0002-8039-0699)
- Rachel Heon‐Roberts (ORCID: https://orcid.org/0000-0001-9723-2227)
- Hjalte Gram (ORCID: https://orcid.org/0000-0001-6516-5189)
- Poul Henning Jensen (ORCID: https://orcid.org/0000-0002-4439-9020)
- Anderson Souza Oliveira (ORCID: https://orcid.org/0000-0003-2186-8100)
- Kristine Freude (ORCID: https://orcid.org/0000-0001-9480-2386)
- L. Winkelmann
Institutions
- University of Copenhagen (DK)
- University of Southern Denmark (DK)
- Aarhus University (DK)
- Odense University Hospital (DK)
- University of Oxford (GB)
- Danish Pain Research Center (DK)
- Aalborg University (DK)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-06-21
- DOI
- https://doi.org/10.1038/s41531-025-01038-4
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Jascha Fonden
- Lundbeckfonden
- A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal
- Syddansk Universitet
- H. Lundbeck A/S
- Parkinsonfonden
- Fonden til Lægevidenskabens Fremme